BACKGROUND: ICA-105665(PF-04895162) is an orally administered Kv7 ion channel modulator for the treatment of epilepsy. Since epilepsy treatment typically involves multiple co-administered therapies, the interaction between ICA-105665 and enzyme inducing antiepileptic drugs (EIAEDs) was evaluated in a small number of subjects in a Phase I study. The aim of our work was to evaluate the clinical drug-drug interaction (DDI) by using a PBPK model to inform the clinical development of ICA-105665.METHODS: A mechanistic PBPK model of ICA-105665 was developed and modeling assumptions and parameters were verified using clinical data from SAD studies in healthy volunteers. The PBPK model was used to simulate potential clinical DDI upon co-administration with EIAEDs, phenytoin and carbamazepine. The pharmacokinetics of ICA-105665 were evaluated in 5 epilepsy subjects also taking EIAEDs (phenytoin n=1, carbamazepine n=3 and phenobarbital n=1). The estimated DDIs from PBPK modeling were compared with results from the small clinical study.RESULTS: The ICA-105665 mechanistic PBPK model predicted an AUC ratio (AUCi/AUC) of 0.6 following co-administration with carbamazepine or phenytoin. In the Phase I study, the observed mean AUC ratio was 0.66 (AUC of EIAEDs cohort/AUC of non EIAEDs cohort). However, high inter-subject variability was observed in the EIAED cohort, primarily due to a subject receiving concomitant phenytoin (300 mg BID).CONCLUSION: PBPK modeling predicts a significant DDI upon co-administration with EIAEDs. The results from the small clinical study were in-line with the prediction. However, additional evaluation with larger sample size is needed to assess the impact of EIAEDs on the pharmacokinetics of ICA-105665 due to the high degree of inter-subject variability.